Expression of Intron-containing HIV-1 RNA Induces NLRP1 Inflammasome Activation in Myeloid Cells

Jalloh, S.; Hughes, I. K.; Akiyama, H.; Gojanovich, A.; Quinones, A.; Yang, M.; Henderson, A. J.; Mostoslavsky, G.; Gummuluru, S.

doi:10.1101/2024.12.23.630103

bioRxiv · 10.1101/2024.12.23.630103

Expression of Intron-containing HIV-1 RNA Induces NLRP1 Inflammasome Activation in Myeloid Cells

Jalloh, S.·Hughes, I. K.·Akiyama, H.·Gojanovich, A.·Quinones, A.·Yang, M.·Henderson, A. J.·Mostoslavsky, G.·Gummuluru, S.

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Abstract

Despite the success of antiretroviral therapy (ART) in suppressing plasma viremia in people living with human immunodeficiency virus type-1 (HIV-1), persistent viral RNA expression in tissue reservoirs is observed and can contribute to HIV-1-induced immunopathology and comorbidities. Infection of long-lived innate immune cells, such as tissue-resident macrophages and microglia may contribute to persistent viral RNA production and chronic inflammation. We recently reported that de-novo cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) in macrophages and microglia leads to MDA5 and MAVS-dependent innate immune sensing and induction of type I IFN responses, demonstrating that HIV icRNA is a pathogen-associated molecular pattern (PAMP). In this report, we show that cytoplasmic expression of HIV-1 icRNA also induces NLRP1 inflammasome activation and IL-1{beta} secretion in macrophages and microglia in a RLR- and endosomal TLR-independent manner. Infection of both macrophages and microglia with either replication-competent or single-cycle HIV-1 induced IL-1{beta} secretion, which was attenuated when cytoplasmic expression of viral icRNA was prevented. While IL-1{beta} secretion was blocked by treatment with caspase-1 inhibitors or knockdown of NLRP1 or caspase-1 expression in HIV- infected macrophages, overexpression of NLRP1 significantly enhanced IL-1{beta} secretion in an HIV-icRNA-dependent manner. Immunoprecipitation analysis revealed interaction of HIV-1 icRNA, but not multiply-spliced HIV-1 RNA, with NLRP1, suggesting that HIV-1 icRNA sensing by NLRP1 is sufficient to trigger inflammasome activation. Together, these findings reveal a pathway of NLRP1 inflammasome activation induced by de novo expressed HIV icRNA in HIV- infected myeloid cells.

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Jalloh, S., Hughes, I. K., Akiyama, H., Gojanovich, A., Quinones, A., Yang, M., Henderson, A. J., Mostoslavsky, G., Gummuluru, S.. 2024-12-23. Expression of Intron-containing HIV-1 RNA Induces NLRP1 Inflammasome Activation in Myeloid Cells. https://doi.org/10.1101/2024.12.23.630103

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